The terms cannabinoid or cannabimimetic compound apply to compounds which produce a physiological effect similar to that of the plant Cannabis Sativa, or a compound that has affinity for the cannabinoid receptors CB.sub.1 or CB.sub.2. See Matsuda, L.; Lolait, S. J.; Brownstein, M. J.; Young, A. C.; Bonner, T. I. Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature, 1990, 346, 561-564: Munro, S.; Thomas, K. L.; Abu-Shaar, M. Molecular characterization of the peripheral receptor of cannabinoids. Nature, 1993, 1993, 61-65. Examples of such compounds are .DELTA..sup.9 -THC and its analogs (Razdan, R. K. Structure activity relationship in the cannabinoids. Pharmacol. Rev., 1986, 38, 75-149), WIN-55212-2 and its analogs (D'Ambra, T. E.; Estep, K. G.; Bell, M. R.; Eissenstat, M. A.; Josef, K. A.; Ward, S. J.; Haycock, D. A.; Baizman, E. R.; Casiano, F. M.; Beglin, N. C.; Chippad, S. M.; Grego, J. D.; Kullnig, R. K.; Daley, G. T. Conformationnaly restrained analogues of Pravadoline: Nanomolar potent, enantioselective, aminoalkylindole agonist of the cannabinoid receptor. J. Med. Chem., 1992, 35, 124-135: Bell, M. R.; D'Ambra, T. E.; Kumar, V.; Eissenstat, M. A.; Hermann, J. L.; Wetzel, J. R.; Rosi, D.; Philion, R. E.; Daum, S. J.; Hlasta, D. J.; Kullnig, R. K.; Ackerman, J. H.; Haubrich, D. R.; Luttinger, D. A.; Baizman, E. R.; Miller, M. S.; Ward, S. J. Antinociceptive aminoalkylindoles. J. Med. Chem., 1991, 34, 1099-1100), CP-55940 and its analogs (Johnson, M. R.; Melvin, L. S. The discovery of non-classical cannabinoid analgetics. In "Cannabinoids as therapeutic agents", 1986, Mechoulam, R., Ed., CRC Press: Boca Raton Fla., pp.121-145), SR141716A and its analogs (Barth, F.; Casellas, P.; Congy, C.; Martinez, S.; Rinaldi, M. Nouveaux derives du pyrazole, procede pour leur preparation et composition pharmaceutiques les contenant. French Patent 2692575-A1, 1992: Barth, F.; Heaulme, M.; Shire, D.; Calandra, B.; Congy, C.; Martinez, S.; Maruani, J.; Neliat, G.; Caput, D.; Ferrara, P.; Soubrie, P.; Breliere, J-C.; Le Fur, G.; Rinaldi-Carmona, M. SR141716A, a potent and selective antagonist of the brain cannabinoid receptor. International Cannabis Research Society Conference Abstract, July 1994, L'EstErel, Canada, p. 33), and anandamide (Devane, W. A.; Hanus, L.; Breuer, A.; Pertwee, R. G.; Stevenson, L. A.; Griffin, G.; Gibson, D.; Mandelbaum, A.; Etinger, A.; Mechoulam, R. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science, 1992, 258, 1946-1949) and its analogs. Anandamide has been termed the endogenous ligand of the CB.sub.1 receptor, as it is synthesized near its site of action and is potent and selective for the CB.sub.1 receptor.
The biological activity of cannabinoids has been extensively reviewed. See Hollister, L. E. Health aspects of Cannabis. Pharmacol. Rev., 1986, 38, 1-20. Their usefulness in various disease states has been discussed. See The therapeutic potential of marihuana. Cohen, S. and Stillman, R. C., eds. Plenum: New York, 1976.
Additionally, U.S. Pat. Nos. 4,973,587 and 5,013,837 (Ward et al.) disclose compounds of formula 1: ##STR1## having antiglaucoma compositions where: R.sub.2 is hydrogen, lower alkyl, chloro or fluoro;
R.sub.3 is phenyl ( or phenyl substituted by from one to three substituents selected from halogen, lower alkoxy, lower alkoxymethyl, hydroxy, lower alkyl, amino, lower alkylamino, di-lower alkylamino or lower alkylmercapto), methylenedioxyphenyl, benzyl, styryl, lower alkoxystyryl, 1- or 2-naphthyl,) or 1- or 2-naphthyl substituted by from one to two substituents selected from lower alkyl, lower alkoxy, halo or cyano), (1H-imidazol-1-yl)naphthyl, 2-(1-naphthyl)ethenyl, 1-(1,2,3,4-tetrahydronaphthyl),anthryl, phenanthryl, pyrenyl,2-, 3-, 4-, 5-, 6- or 7-benzo[b]furyl, 2or 3-benzo[b]thienyl, 5-(1H-benzimidazolyl) or 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl; PA1 R.sub.4 is hydrogen or lower alkyl, hydroxy, lower alkoxy or halo in the 4-, 5-, 6- or 7-positions; PA1 X is O or S; PA1 Alk is lower alkylene having the formula (CH.sub.2).sub.n where n is the integer 2 or 3, or such lower-alkylene substituted by a lower-alkyl group; and PA1 N=B is N,N-di-lower alkylamino, 4-morpholinyl, 2-lower alkyl-4-morpholinyl, 3-lower alkylmorpholinyl, 1-pyrrolidinyl, 1-piperidinyl or 3-hydroxy-1-piperidinyl. PA1 R.sub.3 is hydrogen or lower alkyl; PA1 Alk is lower alkylene containing from two to four carbon atoms. PA1 R.sub.2 is hydrogen, lower alkyl; PA1 R.sub.3 is phenyl ( or phenyl substituted by from one to three substituents selected from halogen, lower alkoxy, hydroxy, lower alkyl, nitro, amino, lower alkylamino, di-lower alkylamino, loweralkylmercapto, lower alkylsulfinyl, lower alkylsulfonyl and methylenedioxy), 2- or 4-biphenyl or 1- or 2-naphthyl (or 1- or 2-naphthyl substituted by from one to two substituents selected from lower alkyl, lower alkoxy, halogen, lower alkylmercapto, lower alkylsulfinyl, lower alkylsulfonyl and trifluoromethyl); PA1 R.sub.4 is hydrogen or from one to two substituents selected from loweralkyl, hydroxy, lower alkoxy, and halogen at the 4-, 5-, 6- or 7- positions; PA1 Alk is lower alkylene containing from two to four carbon atoms which may contain a lower alkyl group; PA1 n is 0 or 1; PA1 Het is an aliphatic heterocycle, 2-piperazinyl and 2-indolinyl. PA1 R.sup.2-4 is independently, H, lower alkyl, lower fluorinated alkyl, halogen, NO.sub.2, CN, --(CR.sup.7.sub.2).sub.m --OR.sup.1,--(CR.sup.7.sub.2).sub.m -- S(O)nR.sup.6.sub.2, or --(CR.sup.7.sub.2)m--R.sup.6 ; PA1 R.sup.5 is H, lower alkyl, aryl, or benzyl; PA1 R.sup.6 is lower alkyl, aryl, benzyl, or N(R.sup.5).sub.2 ; PA1 R.sup.7 is H, or lower alkyl; R.sup.8 is R.sup.7, lower fluorinated alkyl, halogen, OR.sup.7, or lower alkyl thio; PA1 R.sup.9 is R.sup.7, lower fluorinated alkyl, halogen, OR.sup.7, or lower alkyl thio; PA1 Q.sub.1 is H, OR.sup.7, CHO, CN, CO.sub.2 R.sup.7, C(O)SR.sup.7, S(O).sub.n R.sup.6, HET or N(R.sup.7).sub.2, wherein two R.sup.7 groups may be joined to form a pyrrolidine, piperidine, piperazine, morpholine or thiomorpholine ring and their quaternary methyl ammonium salts; PA1 Q.sub.2 is phenyl, naphthyl, quinolinyl, furanyl, thienyl, pyridinyl, anthracyl, benzothienyl, benzofuranyl or thieno[3,2-b]-pyridinyl, mono-, di- or trisubstituted with R.sup.8 ; PA1 HET is is a diradical of benzene, thiazole, thiophene, or furan, substituted with one or two R.sup.9 groups; PA1 Z is CO or a bond. PA1 m is 0-6; and PA1 n is 0,1, or 2. PA1 R.sup.1 is H, lower alkyl, or lower fluorinated alkyl; PA1 R.sup.2-4 is independently H, lower alkyl, OR.sup.1, halogen, or lower fluorinated alkyl; PA1 R.sup.7 is H, or lower alkyl; and PA1 Q.sub.1 is morpholine, piperazine, piperidine, or pyrrolidine. PA1 R.sup.1 is lower alkyl; PA1 R.sup.2-4 is independently is H, or OR.sup.1 ; PA1 R.sub.7 is H; PA1 Q.sub.1 is morpholine; PA1 m is 2; and PA1 Z is a bond. PA1 1--various ocular disorders such as glaucoma. PA1 2--pulmonary disorders including diseases such as asthma, chronic bronchitis and related airway diseases. PA1 3--allergies and allergic reactions such as allergic rhinitis, contact dermatitis, allergic conjunctivitis and the like. PA1 4--inflammation such as arthritis or inflammatory bowel disease. PA1 5--pain. PA1 6--disorders of the immune system such as lupus, AIDS, etc. PA1 7--allograft rejection. PA1 8--central nervous system diseases such as Tourette's syndrome, Parkinson's disease, Huntingdon's disease, epilepsy, various psychotic afflictions such as depression, manic depression, etc. PA1 9--vomiting, and nausea and vertigo, especially in the case of chemotherapy patients. PA1 (i) all operations are carded out at room or ambient temperature, that is, at a temperature in the range 18.degree.-25.degree. C.; PA1 (ii) evaporation of solvent is carried out using a rotary evaporator under reduced pressure (600-4000 pascals: 4.5-30 mm Hg) with a bath temperature of up to 60.degree. C.; PA1 (iii) the course of reactions is followed by thin layer chromatography (TLC) and reaction times are given for illustration only; PA1 (iv) melting points are uncorrected and `d` indicates decomposition; the melting points given are those obtained for the materials prepared as described; polymorphism may result in isolation of materials with different melting points in some preparations; PA1 (v) the structure and purity of all final products are assured by at least one of the following techniques: TLC, mass spectrometry, nuclear magnetic resonance (NMR) spectrometry, or microanalytical data; PA1 (vi) yields are given for illustration only; PA1 (vii) when given, NMR data are in the form of delta (.delta.) values for major diagnostic protons, given in parts per million (ppm) relative to tetramethylsilane (TMS) as internal standard, determined at 300 MHz or 400 MHz using the indicated solvent; conventional abbreviations used for signal shape are: s. singlet; d. doublet; t. triplet; m. multiplet; br. broad; etc.: in addition "Ar" signifies an aromatic signal; PA1 (viii) chemical symbols have their usual meanings; the following abbreviations have also been used: v (volume), w (weight), b.p. (boiling point), m.p. (melting point), L (liter(s)), mL
U.S. Pat. No. 5,081,122 (Ward) discloses compounds of formula 2: ##STR2## having antiglaucoma compositions where: Ar is lower alkoxyphenyl or 1- or 2-naphthyl;
The present compounds differ from Ward's (formula 1 and 2) primarily in having a carbonyl on the nitrogen of the indole while it is at the 4-position in the case of the U.S. Pat. No. 5,081,122.
EP 0 444 451 generically discloses a compound of formula ##STR3## useful as analgesic, anti-rheumatic, anti-inflammatory or anti-glaucoma agents where:
The present compound differs from formula 3 primarily in having a carbonyl on the nitrogen of the indole.
U.S. Pat. No. 3,489,770 generically discloses compound having the following formula 4: ##STR4##
The compounds are said to have anti-inflammatory, hypotensive, hypoglycemic and CNS activities. Although not within the ambit of the above-defined genus, the patent also discloses a variety of species where R.sub.2 is an arylcarbonyl group.
British Patent 1,374,414 and U.S. Pat. No. 4,021,431 generically discloses compounds having the following structural formula 5: ##STR5##
The compounds are useful as anti-inflammatory agents. Although not within the ambit of the above-defined genus, the patent also discloses a variety of species where A is an arylcarbonyl group.